Detecting Psychological Interventions Using Bilateral Electromyographic Wearable Sensors.

This study investigated the impact of auditory stimuli on muscular activation patterns using wearable surface electromyography (EMG) sensors. Employing four key muscles (Sternocleidomastoid Muscle (SCM), Cervical Erector Muscle (CEM), Quadricep Muscles (QMs), and Tibialis Muscle (TM)) and time domain features, we differentiated the effects of four interventions: silence, music, positive reinforcement, and negative reinforcement. The results demonstrated distinct muscle responses to the interventions, with the SCM and CEM being the most sensitive to changes and the TM being the most active and stimulus dependent. Post hoc analyses revealed significant intervention-specific activations in the CEM and TM for specific time points and intervention pairs, suggesting dynamic modulation and time-dependent integration. Multi-feature analysis identified both statistical and Hjorth features as potent discriminators, reflecting diverse adaptations in muscle recruitment, activation intensity, control, and signal dynamics. These features hold promise as potential biomarkers for monitoring muscle function in various clinical and research applications. Finally, muscle-specific Random Forest classification achieved the highest accuracy and Area Under the ROC Curve for the TM, indicating its potential for differentiating interventions with high precision. This study paves the way for personalized neuroadaptive interventions in rehabilitation, sports science, ergonomics, and healthcare by exploiting the diverse and dynamic landscape of muscle responses to auditory stimuli.

Establishing RTS,S/AS01 as a benchmark for comparison to next-generation malaria vaccines in a mouse model.

New strategies are needed to reduce the incidence of malaria, and promising approaches include vaccines targeting the circumsporozoite protein (CSP). To improve upon the malaria vaccine, RTS,S/AS01, it is essential to standardize preclinical assays to measure the potency of next-generation vaccines against this benchmark. We focus on RTS,S/AS01-induced antibody responses and functional activity in conjunction with robust statistical analyses. Transgenic Plasmodium berghei sporozoites containing full-length P. falciparum CSP (tgPb-PfCSP) allow two assessments of efficacy: quantitative reduction in liver infection following intravenous challenge, and sterile protection from mosquito bite challenge. Two or three doses of RTS,S/AS01 were given intramuscularly at 3-week intervals, with challenge 2-weeks after the last vaccination. Minimal inter- and intra-assay variability indicates the reproducibility of the methods. Importantly, the range of this model is suitable for screening more potent vaccines. Levels of induced anti-CSP antibody 2A10 equivalency were also associated with activity: 105 µg/mL (95% CI: 68.8, 141) reduced liver infection by 50%, whereas 285 µg/mL (95% CI: 166, 404) is required for 50% sterile protection from mosquito bite challenge. Additionally, the liver burden model was able to differentiate between protected and non-protected human plasma samples from a controlled human malaria infection study, supporting these models' relevance and predictive capability. Comparison in animal models of CSP-based vaccine candidates to RTS,S/AS01 is now possible under well controlled conditions. Assessment of the quality of induced antibodies, likely a determinant of durability of protection in humans, should be possible using these methods.

Cognitive and Emotional Responses to Chronic Obstructive Pulmonary Disease Exacerbations and Patterns of Care Seeking.

Rationale: Cognitive and emotional responses associated with care seeking for chronic obstructive pulmonary disease (COPD) exacerbations are not well understood.Objectives: We sought to define care-seeking profiles based on whether and when U.S. veterans seek care for COPD exacerbations and compare cognitive and emotional responses with exacerbation symptoms across the profiles.Methods: This study analyzes data from a 1-year prospective observational cohort study of individuals with COPD. Cognitive and emotional responses to worsening symptoms were measured with the Response to Symptoms Questionnaire, adapted for COPD. Seeking care was defined as contacting or visiting a healthcare provider or going to the emergency department. Participants were categorized into four care-seeking profiles based on the greatest delay in care seeking for exacerbations when care was sought: 0-3 days (early), 4-7 days (short delay), >7 days (long delay), or never sought care for any exacerbation. The proportion of exacerbations for which participants reported cognitive and emotional responses was estimated for each care-seeking profile, stratified by the timing of when care was sought.Results: There were 1,052 exacerbations among 350 participants with Response to Symptoms Questionnaire responses. Participants were predominantly male (96%), and the mean age was 69.3 ± 7.2 years. For the 409 (39%) exacerbations for which care was sought, the median delay was 3 days. Those who sought care had significantly more severe COPD (forced expiratory volume in 1 s, modified Medical Research Council dyspnea scale) than those who never sought care. Regardless of the degree of delay until seeking care at one exacerbation, participants consistently reported experiencing serious symptoms if they sought care compared with events for which participants did not seek care (e.g., among early care seekers when care was sought, 36%; when care was not sought, 25%). Similar findings were seen in participants' assessment of the importance of getting care (e.g., among early care seekers when care was sought, 90%; when care was not sought, 52%) and their assessment of anxiety about the symptoms (e.g., among early care seekers when care was sought, 33%; when care was not sought, 17%).Conclusions: Delaying or not seeking care for COPD exacerbations was common. Regardless of care-seeking profile, cognitive and emotional responses to symptoms when care was sought differed from responses when care was not sought. Emotional and cognitive response to COPD exacerbations should be considered when developing individualized strategies to encourage seeking care for exacerbations.Clinical trial registered with www.clinicaltrials.gov (NCT02725294).

Predictors of Patient-reported and Pharmacy Refill Measures of Maintenance Inhaler Adherence in Veterans with Chronic Obstructive Pulmonary Disease.

Rationale: Suboptimal adherence to inhaled medications in patients with chronic obstructive pulmonary disease (COPD) remains a challenge. Objectives: To examine the sociodemographic and clinical characteristics and medication beliefs associated with adherence measured by self-report and pharmacy data. Methods: A cross-sectional analysis of data from a prospective observational cohort study of patients with COPD was completed. Participants underwent spirometry and completed questionnaires regarding sociodemographic data, inhaler use, dyspnea, social support, psychological and medical comorbidities, and medication beliefs (Beliefs about Medicines Questionnaire [BMQ]). Self-reported adherence to inhaled medications was measured with the Adherence to Refills and Medications Scale (ARMS), and pharmacy-based adherence was calculated from administrative data using the ReComp score. Multivariable linear regression was used to examine the sociodemographic, clinical, and medication-belief factors associated with both adherence measures. Results: Among 269 participants with ARMS and ReComp data, adherence was the same for each measure (38.3%), but only 18% of participants were adherent by both measures. In multivariable adjusted analysis, a 10-year increase in age (ß = 0.54; 95% confidence interval, 0.14-0.94) and the number of maintenance inhalers used (ß = 0.53; 0.04-1.02) were associated with increased adherence by self-report. Improved ReComp adherence was associated with chronic prednisone use (ß = 0.18; 0.04-0.31) and the number of maintenance inhalers used (ß = 0.11; 0.05-0.17). In adjusted analyses examining patient beliefs about medications, increases in the COPD-specific BMQ concerns score (ß = -0.10; -0.17 to -0.02) were associated with reduced self-reported adherence. No significant associations between ReComp adherence and BMQ score were found in adjusted analyses. Conclusions: Adherence to inhaled COPD medications was poor as measured by self-report or pharmacy refill data. There were notable differences in factors associated with adherence based on the method of adherence measurement. Older age, chronic prednisone use, the number of prescribed maintenance inhalers used, and patient beliefs about medication safety were associated with adherence. Overall, fewer variables were associated with adherence as measured based on pharmacy refills. Pharmacy refill-based and self-reported adherence may measure distinct aspects of adherence and may be affected by different factors. These results also underscore the importance of addressing patient beliefs when developing interventions to improve medication adherence.

Novel antibody competition binding assay identifies distinct serological profiles associated with protection.

Introduction: Pre-erythrocytic malaria vaccines hold the promise of inducing sterile protection thereby preventing the morbidity and mortality associated with Plasmodium infection. The main surface antigen of P. falciparum sporozoites, i.e., the circumsporozoite protein (CSP), has been extensively explored as a target of such vaccines with significant success in recent years. Systematic adjuvant selection, refinements of the immunization regimen, and physical properties of the antigen may all contribute to the potential of increasing the efficacy of CSP-based vaccines. Protection appears to be dependent in large part on CSP antibodies. However due to a knowledge gap related to the exact correlates of immunity, there is a critical need to improve our ability to down select candidates preclinically before entering clinical trials including with controlled human malaria infections (CHMI). Methods: We developed a novel multiplex competition assay based on well-characterized monoclonal antibodies (mAbs) that target crucial epitopes across the CSP molecule. This new tool assesses both, quality and epitope-specific concentrations of vaccine-induced antibodies by measuring their equivalency with a panel of well-characterized, CSP-epitope-specific mAbs. Results: Applying this method to RTS,S-immune sera from a CHMI trial demonstrated a quantitative epitope-specificity profile of antibody responses that can differentiate between protected vs. nonprotected individuals. Aligning vaccine efficacy with quantitation of the epitope fine specificity results of this equivalency assay reveals the importance of epitope specificity. Discussion: The newly developed serological equivalence assay will inform future vaccine design and possibly even adjuvant selection. This methodology can be adapted to other antigens and disease models, when a panel of relevant mAbs exists, and could offer a unique tool for comparing and down-selecting vaccine formulations.

Association between self-reported falling risk and risk of hospitalization for patients with chronic obstructive pulmonary disease.

RATIONALE: The association between self-report falling risk in persons with COPD and hospitalization has not been previously explored. OBJECTIVE: To examine whether self-reported risk is associated with hospitalizations in patients with COPD. METHODS: A secondary analysis from a prospective observational cohort study of veterans with COPD. Participants completed questions from the Stopping Elderly Accidents, Deaths and Injuries (STEADI) tool kit at either baseline or at the end of the 12-month study. A prospective or cross-sectional analysis examined the association between responses to the STEADI questions and risk of all-cause or COPD hospitalizations. RESULTS: Participants (N = 388) had a mean age of 69.6 ± 7.5 years, predominately male (96 %), and 144 (37.1 %) reported having fallen in the last year. More than half reported feeling unsteady with walking (52.6 %) or needing to use their arms to stand up from a chair (61.1 %). A third were concerned about falling (33.3 %). Three questions were associated with all-cause (not COPD) hospitalization in both unadjusted and adjusted cross-sectional analysis (N = 213): "fallen in the past year" (IRR 1.77, 95 % CI 1.10 to 2.86); "unsteady when walking" (IRR 1.88, 95 % CI 1.14 to 3.10); "advised to use a cane or walker" (IRR 1.89, 95 % CI 1.16 to 3.08). CONCLUSIONS: The prevalence of self-reported falling risk was high in this sample of veterans with COPD. The association between falling risk and all-cause hospitalization suggests that non-COPD hospitalizations can negatively impact intrinsic risk factors for falling. Further research is needed to clarify the effects of all-cause hospitalization on falling risk in persons with COPD.

Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection.

The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies and highlight key features underlying the potent protection of this antibody family.

Extending the range of Plasmodium falciparum transmission blocking antibodies.

Recent work demonstrating that asymptomatic carriers of P. falciparum parasites make up a large part of the infectious reservoir highlights the need for an effective malaria vaccine. Given the historical challenges of vaccine development, multiple parasite stages have been targeted, including the sexual stages required for transmission. Using flow cytometry to efficiently screen for P. falciparum gamete/zygote surface reactivity, we identified 82 antibodies that bound live P. falciparum gametes/zygotes. Ten antibodies had significant transmission-reducing activity (TRA) in a standard membrane feeding assay and were subcloned along with 9 nonTRA antibodies as comparators. After subcloning, only eight of the monoclonals obtained have significant TRA. These eight TRA mAbs do not recognize epitopes present in any of the current recombinant transmission-blocking vaccine candidates, Pfs230D1M, Pfs48/45.6C, Pf47 D2 and rPfs25. One TRA mAb immunoprecipitates two surface antigens, Pfs47 and Pfs230, that are expressed by both gametocytes and gametes/zygotes. These two proteins have not previously been reported to associate and the recognition of both by a single TRA mAb suggests the Pfs47/Pfs230 complex is a new vaccine target. In total, Pfs230 was the dominant target antigen, with five of the eight TRA mAbs and 8 of 11 nonTRA gamete/zygote surface reactive mAbs interacting with Pfs230. Of the three remaining TRA mAbs, two recognized non-reduced, parasite-produced Pfs25 and one bound non-reduced, parasite-produced Pfs48/45. None of the TRA mAbs bound protein on an immunoblot of reduced gamete/zygote extract and two TRA mAbs were immunoblot negative, indicating none of the new TRA epitopes are linear. The identification of eight new TRA mAbs that bind epitopes not included in any of the constructs currently under advancement as transmission-blocking vaccine candidates may provide new targets worthy of further study.

Safety, tolerability, and immunogenicity of inactivated poliovirus vaccine with or without E.coli double mutant heat-labile toxin (dmLT) adjuvant in healthy adults; a phase 1 randomized study.

BACKGROUND: Inactivated trivalent poliovirus vaccine (IPV) induces humoral immunity, which protects against paralytic poliomyelitis but does not induce sufficient mucosal immunity to block intestinal infection. We assessed the intestinal immunity in healthy adults in Belgium conferred by a co-formulation of IPV with the mucosal adjuvant double mutant Labile Toxin (dmLT) derived from Escherichia coli. METHODS: Healthy fully IPV-vaccinated 18-45-year-olds were randomly allocated to three groups: on Day 1 two groups received one full dose of IPV (n = 30) or IPV + dmLT (n = 30) in a blinded manner, and the third received an open-label dose of bivalent live oral polio vaccine (bOPV types 1 and 3, n = 20). All groups received a challenge dose of bOPV on Day 29. Participants reported solicited and unsolicited adverse events (AE) using study diaries. Mucosal immune responses were measured by fecal neutralization and IgA on Days 29 and 43, with fecal shedding of challenge viruses measured for 28 days. Humoral responses were measured by serum neutralizing antibody (NAb). RESULTS: Solicited and unsolicited AEs were mainly mild-to-moderate and transient in all groups, with no meaningful differences in rates between groups. Fecal shedding of challenge viruses in both IPV groups exceeded that of the bOPV group but was not different between IPV and IPV + dmLT groups. High serum NAb responses were observed in both IPV groups, alongside modest levels of fecal neutralization and IgA. CONCLUSIONS: Addition of dmLT to IPV administered intramuscularly neither affected humoral nor intestinal immunity nor decreased fecal virus shedding following bOPV challenge. The tolerability of the dose of dmLT used in this study may allow higher doses to be investigated for impact on mucosal immunity. Registered on ClinicalTrials.gov - NCT04232943.

Complexity and Challenges of the Clinical Diagnosis and Management of Long COVID.

Importance: There is increasing recognition of the long-term health effects of SARS-CoV-2 infection (sometimes called long COVID). However, little is yet known about the clinical diagnosis and management of long COVID within health systems. Objective: To describe dominant themes pertaining to the clinical diagnosis and management of long COVID in the electronic health records (EHRs) of patients with a diagnostic code for this condition (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code U09.9). Design, Setting, and Participants: This qualitative analysis used data from EHRs of a national random sample of 200 patients receiving care in the Department of Veterans Affairs (VA) with documentation of a positive result on a polymerase chain reaction (PCR) test for SARS-CoV-2 between February 27, 2020, and December 31, 2021, and an ICD-10 diagnostic code for long COVID between October 1, 2021, when the code was implemented, and March 1, 2022. Data were analyzed from February 5 to May 31, 2022. Main Outcomes and Measures: A text word search and qualitative analysis of patients' VA-wide EHRs was performed to identify dominant themes pertaining to the clinical diagnosis and management of long COVID. Results: In this qualitative analysis of documentation in the VA-wide EHR, the mean (SD) age of the 200 sampled patients at the time of their first positive PCR test result for SARS-CoV-2 in VA records was 60 (14.5) years. The sample included 173 (86.5%) men; 45 individuals (22.5%) were identified as Black and 136 individuals (68.0%) were identified as White. In qualitative analysis of documentation pertaining to long COVID in patients' EHRs 2 dominant themes were identified: (1) clinical uncertainty, in that it was often unclear whether particular symptoms could be attributed to long COVID, given the medical complexity and functional limitations of many patients and absence of specific markers for this condition, which could lead to ongoing monitoring, diagnostic testing, and specialist referral; and (2) care fragmentation, describing how post-COVID-19 care processes were often siloed from and poorly coordinated with other aspects of care and could be burdensome to patients. Conclusions and Relevance: This qualitative study of documentation in the VA EHR highlights the complexity of diagnosing long COVID in clinical settings and the challenges of caring for patients who have or are suspected of having this condition.

Vaccine co-display of CSP and Pfs230 on liposomes targeting two Plasmodium falciparum differentiation stages.

A vaccine targeting multiple stages of the Plasmodium falciparum parasite life cycle is desirable. The sporozoite surface Circumsporozoite Protein (CSP) is the target of leading anti-infective P. falciparum pre-erythrocytic vaccines. Pfs230, a sexual-stage P. falciparum surface protein, is currently in trials as the basis for a transmission-blocking vaccine, which inhibits parasite development in the mosquito vector. Here, recombinant full-length CSP and a Pfs230 fragment (Pfs230D1+) are co-displayed on immunogenic liposomes to induce immunity against both infection and transmission. Liposomes contain cobalt-porphyrin phospholipid (CoPoP), monophosphoryl lipid A and QS-21, and rapidly bind His-tagged CSP and Pfs230D1+ upon admixture to form bivalent particles that maintain reactivity with conformational monoclonal antibodies. Use of multicolor fluorophore-labeled antigens reveals liposome binding upon admixture, stability in serum and enhanced uptake in murine macrophages in vitro. Bivalent liposomes induce humoral and cellular responses against both CSP and Pfs230D1+. Vaccine-induced antibodies reduce parasite numbers in mosquito midguts in a standard membrane feeding assay. Mice immunized with liposome-displayed antigens or that passively receive antibodies from immunized rabbits have reduced parasite liver burden following challenge with transgenic sporozoites expressing P. falciparum CSP.

Safety, tolerability, and Plasmodium falciparum transmission-reducing activity of monoclonal antibody TB31F: a single-centre, open-label, first-in-human, dose-escalation, phase 1 trial in healthy malaria-naive adults.

BACKGROUND: Malaria elimination requires interruption of the highly efficient transmission of Plasmodium parasites by mosquitoes. TB31F is a humanised monoclonal antibody that binds the gamete surface protein Pfs48/45 and inhibits fertilisation, thereby preventing further parasite development in the mosquito midgut and onward transmission. We aimed to evaluate the safety and efficacy of TB31F in malaria-naive participants. METHODS: In this open-label, first-in-human, dose-escalation, phase 1 clinical trial, healthy, malaria-naive, adult participants were administered a single intravenous dose of 0·1, 1, 3, or 10 mg/kg TB31F or a subcutaneous dose of 100 mg TB31F, and monitored until day 84 after administration at a single centre in the Netherlands. The primary outcome was the frequency and magnitude of adverse events. Additionally, TB31F serum concentrations were measured by ELISA. Transmission-reducing activity (TRA) of participant sera was assessed by standard membrane feeding assays with Anopheles stephensi mosquitoes and cultured Plasmodium falciparum gametocytes. The trial is registered with Clinicaltrials.gov, NCT04238689. FINDINGS: Between Feb 17 and Dec 10, 2020, 25 participants were enrolled and sequentially assigned to each dose (n=5 per group). No serious or severe adverse events occurred. In total, 33 grade 1 and six grade 2 related adverse events occurred in 20 (80%) of 25 participants across all groups. Serum of all participants administered 1 mg/kg, 3 mg/kg, or 10 mg/kg TB31F intravenously had more than 80% TRA for 28 days or more, 56 days or more, and 84 days or more, respectively. The TB31F serum concentration reaching 80% TRA was 2·1 µg/mL (95% CI 1·9-2·3). Extrapolating the duration of TRA from antibody kinetics suggests more than 80% TRA is maintained for 160 days (95% CI 136-193) following a single intravenous 10 mg/kg dose. INTERPRETATION: TB31F is a well tolerated and highly potent monoclonal antibody capable of completely blocking transmission of P falciparum parasites from humans to mosquitoes. In areas of seasonal transmission, a single dose might cover an entire malaria season. FUNDING: PATH's Malaria Vaccine Initiative.

Heterologous Expression and Evaluation of Novel Plasmodium falciparum Transmission Blocking Vaccine Candidates.

Malaria transmission blocking vaccines (TBV) aim to induce antibodies that can interrupt Plasmodium falciparum development in the mosquito midgut and thereby prevent onward malaria transmission. A limited number of TBV candidates have been identified and only three (Pfs25, Pfs230 and Pfs48/45) have entered clinical testing. While one of these candidates may emerge as a highly potent TBV candidate, it is premature to determine if they will generate sufficiently potent and sustained responses. It is therefore important to explore novel candidate antigens. We recently analyzed sera from naturally exposed individuals and found that the presence and/or intensity of antibodies against 12 novel putative surface expressed gametocyte antigens was associated with transmission reducing activity. In this study, protein fragments of these novel TBV candidates were designed and heterologously expressed in Drosophila melanogaster S2 cells and Lactococcus lactis. Eleven protein fragments, covering seven TBV candidates, were successfully produced. All tested antigens were recognized by antibodies from individuals living in malaria-endemic areas, indicating that native epitopes are present. All antigens induced antigen-specific antibody responses in mice. Two antigens induced antibodies that recognized a native protein in gametocyte extract, and antibodies elicited by four antigens recognized whole gametocytes. In particular, we found that antigen Pf3D7_0305300, a putative transporter, is abundantly expressed on the surface of gametocytes. However, none of the seven novel TBV candidates expressed here induced an antibody response that reduced parasite development in the mosquito midgut as assessed in the standard membrane feeding assay. Altogether, the antigen fragments used in this study did not prove to be promising transmission blocking vaccine constructs, but led to the identification of two gametocyte surface proteins that may provide new leads for studying gametocyte biology.

Potential Explanatory Factors for the Concurrent Experience of Dyspnea and Pain in Patients with COPD.

Previous research has identified unexpectedly strong associations between dyspnea and pain, but the reasons remain unclear. Ascertaining the underlying biological and psychological mechanisms might enhance the understanding of the experience of both conditions, and suggest novel treatments. We sought to elucidate whether demographic factors, disease severity, psychological symptoms and biomarkers might account for the association between pain and dyspnea in individuals with COPD. We analyzed data from 301 patients with COPD who were followed in a prospective longitudinal observational study over 2 years. Measures included self-reported dyspnea and pain, pulmonary function tests, serum levels of inflammatory cytokines, measures of physical deconditioning, and scales for depression and anxiety. Analyses involved cross-sectional and longitudinal linear regression models. Pain and dyspnea were strongly correlated cross-sectionally (r = 0.77, 95% CI 0.72-0.82) and simultaneously across time (r = 0.42, 95% CI 0.28-0.56). Accounting for any of the other health factors only slightly mitigated the associations. Symptoms of pain and dyspnea thus may be fundamentally linked in COPD, rather than being mediated by common biological, psychological, or functional factors. From the patient's perspective, pain and dyspnea may be part of the same essential experience. It is possible that treatments for one condition would improve the other.

Identifying Individuals Who Currently Report Feelings of Anxiety Using Walking Gait and Quiet Balance: An Exploratory Study Using Machine Learning.

Literature suggests that anxiety affects gait and balance among young adults. However, previous studies using machine learning (ML) have only used gait to identify individuals who report feeling anxious. Therefore, the purpose of this study was to identify individuals who report feeling anxious at that time using a combination of gait and quiet balance ML. Using a cross-sectional design, participants (n = 88) completed the Profile of Mood Survey-Short Form (POMS-SF) to measure current feelings of anxiety and were then asked to complete a modified Clinical Test for Sensory Interaction in Balance (mCTSIB) and a two-minute walk around a 6 m track while wearing nine APDM mobility sensors. Results from our study finds that Random Forest classifiers had the highest median accuracy rate (75%) and the five top features for identifying anxious individuals were all gait parameters (turn angles, variance in neck, lumbar rotation, lumbar movement in the sagittal plane, and arm movement). Post-hoc analyses suggest that individuals who reported feeling anxious also walked using gait patterns most similar to older individuals who are fearful of falling. Additionally, we find that individuals who are anxious also had less postural stability when they had visual input; however, these individuals had less movement during postural sway when visual input was removed.

Comparison of Moderna versus Pfizer-BioNTech COVID-19 vaccine outcomes: A target trial emulation study in the U.S. Veterans Affairs healthcare system.

Background: mRNA COVID-19 vaccines manufactured by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) have been shown to be efficacious but have not been compared in head-to-head clinical trials. Methods: We designed this observational study to emulate a target trial of COVID-19 vaccination by BNT162b2 versus mRNA-1273 among persons who underwent vaccination in the national U.S. Veterans Affairs (VA) healthcare system from 11/12/2020 to 25/03/2021 using combined VA and Medicare electronic health records. We identified the best matching mRNA-1273 recipient(s) for each BNT162b2 recipient, using exact/coarsened-exact matching (calendar week, VA integrated service network, age buckets and Charlson comorbidity index buckets) followed by propensity score matching. Vaccine recipients were followed from the date of first vaccine dose until 25/08/2021 for the development of SARS-CoV-2 infection, SARS-CoV-2-related hospitalization or SARS-CoV-2-related death. Findings: Each group included 902,235 well-matched vaccine recipients, followed for a mean of 192 days, during which 16,890 SARS-CoV-2 infections, 3591 SARS-CoV-2-related hospitalizations and 381 SARS-CoV-2-related deaths were documented. Compared to BNT162b2, mRNA-1273 recipients had significantly lower risk of SARS-CoV-2 infection (adjusted hazard ratio [aHR] 0.736, 95% CI 0.696-0.779) and SARS-CoV-2-related hospitalization (aHR 0.633, 95% CI 0.562-0.713), which persisted across all age groups, comorbidity burden categories and black/white race. The differences between mRNA-1273 and BNT162b2 in risk of infection or hospitalization were progressively greater when the follow-up period was longer, i.e. extending to March 31, June 30 or August 25, 2021. These differences were more pronounced when we analyzed separately the outcomes that occurred during the follow-up period from July 1 to August 25, 2021 when the Delta variant became predominant in the U.S. (aHR for infection 0.584, 95% CI 0.533-0.639 and aHR for hospitalization 0.387, 95% 0.311-0.482). SARS-CoV-2-related deaths were less common in mRNA-1273 versus BNT162b2 recipients (168 versus 213) but this difference was not statistically significant (aHR 0.808, 95% CI 0.592-1.103). Interpretation: In conclusion, although absolute rates of infection, hospitalization and death in both vaccine groups were low regardless of the vaccine received, our data suggests that compared to BNT162b2, vaccination with mRNA-1273 resulted in significantly lower rates of SARS-CoV-2-infection and SARS-CoV-2-related hospitalization. These differences were greater with longer follow-up time since vaccination and even more pronounced in the Delta variant era. Funding: U.S. Department of Veterans Affairs, grant numbers COVID19-8900-11 and C19 21-278.

A novel CSP C-terminal epitope targeted by an antibody with protective activity against Plasmodium falciparum.

Potent and durable vaccine responses will be required for control of malaria caused by Plasmodium falciparum (Pf). RTS,S/AS01 is the first, and to date, the only vaccine that has demonstrated significant reduction of clinical and severe malaria in endemic cohorts in Phase 3 trials. Although the vaccine is protective, efficacy declines over time with kinetics paralleling the decline in antibody responses to the Pf circumsporozoite protein (PfCSP). Although most attention has focused on antibodies to repeat motifs on PfCSP, antibodies to other regions may play a role in protection. Here, we expressed and characterized seven monoclonal antibodies to the C-terminal domain of CSP (ctCSP) from volunteers immunized with RTS,S/AS01. Competition and crystal structure studies indicated that the antibodies target two different sites on opposite faces of ctCSP. One site contains a polymorphic region (denoted α-ctCSP) and has been previously characterized, whereas the second is a previously undescribed site on the conserved ß-sheet face of the ctCSP (denoted ß-ctCSP). Antibodies to the ß-ctCSP site exhibited broad reactivity with a diverse panel of ctCSP peptides whose sequences were derived from field isolates of P. falciparum whereas antibodies to the α-ctCSP site showed very limited cross reactivity. Importantly, an antibody to the ß-site demonstrated inhibition activity against malaria infection in a murine model. This study identifies a previously unidentified conserved epitope on CSP that could be targeted by prophylactic antibodies and exploited in structure-based vaccine design.

Care-seeking and delay of care during COPD exacerbations.

Patients who receive earlier treatment for acute exacerbations of chronic obstructive pulmonary disease (COPD) have a better prognosis, including earlier symptom resolution and reduced risk of future emergency-department visits (ED) or hospitalizations. However, many patients delay seeking care or do not report worsening symptoms to their healthcare provider. In this study, we aimed to understand how patients perceived their breathing symptoms and identify factors that led to seeking or delaying care for an acute exacerbation of COPD. We conducted semistructured interviews with 60 individuals following a recent COPD exacerbation. Participants were identified from a larger study of outpatients with COPD by purposive sampling by exacerbation type: 15 untreated, 15 treated with prednisone and/or antibiotics in the outpatient setting, 16 treated in an urgent care or ED setting, and 14 hospitalized. Data were analyzed using inductive content analysis. Participants were primarily male (97%) with a mean age of 69.1 ± 6.9 years, mean FEV1 1.42 (±0.63), and mean mMRC dyspnea of 2.7 (±1.1). We identified 4 primary themes: (i) access and attitudinal barriers contribute to reluctance to seek care, (ii) waiting is a typical response to new exacerbations, (iii) transitioning from waiting to care-seeking: the tipping point, and (iv) learning from and avoiding worse outcomes. Interventions to encourage earlier care-seeking for COPD exacerbations should consider individuals' existing self-management approaches, address attitudinal barriers to seeking care, and consider health-system changes to increase access to non-emergent outpatient treatment for exacerbations.Clinical Trial Registration NCT02725294.

Trends Over Time in the Risk of Adverse Outcomes Among Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BACKGROUND: We aimed to describe trends in adverse outcomes among patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between February and September 2020 within a national healthcare system. METHODS: We identified enrollees in the national United States Veterans Affairs healthcare system who tested positive for SARS-CoV-2 between 28 February 2020 and 30 September 2020 (n = 55 952), with follow-up extending to 19 November 2020. We determined trends over time in incidence of the following outcomes that occurred within 30 days of testing positive: hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and death. RESULTS: Between February and July 2020, there were marked downward trends in the 30-day incidence of hospitalization (44.2% to 15.8%), ICU admission (20.3% to 5.3%), mechanical ventilation (12.7% to 2.2%), and death (12.5% to 4.4%), which subsequently plateaued between July and September 2020. These trends persisted after adjustment for sociodemographic characteristics, comorbid conditions, documented symptoms, and laboratory tests, including among subgroups of patients hospitalized, admitted to the ICU, or treated with mechanical ventilation. From February to September, there were decreases in the use of hydroxychloroquine (56.5% to 0%), azithromycin (48.3% to 16.6%), vasopressors (20.6% to 8.7%), and dialysis (11.6% to 3.8%) and increases in the use of dexamethasone (3.4% to 53.1%), other corticosteroids (4.9% to 29.0%), and remdesivir (1.7% to 45.4%) among hospitalized patients. CONCLUSIONS: The risk of adverse outcomes in SARS-CoV-2-positive patients decreased markedly between February and July, with subsequent stabilization from July to September. These trends were not explained by changes in measured baseline patient characteristics and may reflect changing treatment practices or viral pathogenicity.